Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy.

Autor:	Hong X; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Sullivan RJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Kalinich M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Kwan TT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Giobbie-Hurder A; Division of Biostatistics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215., Pan S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., LiCausi JA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Milner JD; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Nieman LT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Wittner BS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Ho U; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Chen T; Division of Biostatistics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215., Kapur R; Center for Bioengineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114., Lawrence DP; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Flaherty KT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Sequist LV; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Ramaswamy S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Miyamoto DT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114.; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Lawrence M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114., Toner M; Center for Bioengineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114.; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Isselbacher KJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu., Maheswaran S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu.; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Haber DA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu.; Howard Hughes Medical Institute, Chevy Chase, MD 20815.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Mar 06; Vol. 115 (10), pp. 2467-2472. Date of Electronic Publication: 2018 Feb 16.
DOI:	10.1073/pnas.1719264115
Abstrakt:	A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived ( n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies. Competing Interests: Conflict of interest statement: Massachusetts General Hospital and the authors have applied for patent protection for the CTC-iChip technology and the molecular signatures of melanoma cells. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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